chr2-70935956-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PVS1_SupportingBP6_Very_StrongBA1

The NM_001692.4(ATP6V1B1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 1,612,178 control chromosomes in the GnomAD database, including 148,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 12699 hom., cov: 32)

Exomes 𝑓: 0.43 ( 135855 hom. )

Consequence

ATP6V1B1
NM_001692.4 start_lost

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.64

Publications

29 publications found

Variant links:

Genes affected

ATP6V1B1 (HGNC:853): (ATPase H+ transporting V1 subunit B1) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain B subunit isoforms and is found in the kidney. Mutations in this gene cause distal renal tubular acidosis associated with sensorineural deafness. [provided by RefSeq, Jul 2008]

ATP6V1B1 links:

VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

VAX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 codons. Genomic position: 70935961. Lost 0.005 part of the original CDS.

BP6

Variant 2-70935956-T-C is Benign according to our data. Variant chr2-70935956-T-C is described in ClinVar as Benign. ClinVar VariationId is 44228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1B1	NM_001692.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 14	ENST00000234396.10	NP_001683.2	P15313

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1B1	ENST00000234396.10 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 14	1	NM_001692.4	ENSP00000234396.4		P15313

Frequencies

GnomAD3 genomes

AF:

0.406

AC:

61728

AN:

151874

Hom.:

12693

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.513

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.377

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.502

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.436

Gnomad OTH

AF:

0.377

GnomAD2 exomes

AF:

0.400

AC:

99661

AN:

249098

AF XY:

0.404

show subpopulations

Gnomad AFR exome

AF:

0.381

Gnomad AMR exome

AF:

0.261

Gnomad ASJ exome

AF:

0.367

Gnomad EAS exome

AF:

0.392

Gnomad FIN exome

AF:

0.495

Gnomad NFE exome

AF:

0.437

Gnomad OTH exome

AF:

0.405

GnomAD4 exome

AF:

0.429

AC:

625783

AN:

1460186

Hom.:

135855

Cov.:

AF XY:

0.427

AC XY:

310307

AN XY:

726338

show subpopulations

African (AFR)

AF:

0.374

AC:

12516

AN:

33450

American (AMR)

AF:

0.267

AC:

11932

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.373

AC:

9716

AN:

26068

East Asian (EAS)

AF:

0.372

AC:

14774

AN:

39664

South Asian (SAS)

AF:

0.377

AC:

32504

AN:

86134

European-Finnish (FIN)

AF:

0.490

AC:

26081

AN:

53228

Middle Eastern (MID)

AF:

0.321

AC:

1849

AN:

5756

European-Non Finnish (NFE)

AF:

0.442

AC:

491388

AN:

1110968

Other (OTH)

AF:

0.415

AC:

25023

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

19248

38495

57743

76990

96238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14822

29644

44466

59288

74110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.406

AC:

61755

AN:

151992

Hom.:

12699

Cov.:

AF XY:

0.409

AC XY:

30354

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.379

AC:

15709

AN:

41456

American (AMR)

AF:

0.316

AC:

4832

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.376

AC:

1303

AN:

3464

East Asian (EAS)

AF:

0.376

AC:

1944

AN:

5164

South Asian (SAS)

AF:

0.357

AC:

1714

AN:

4806

European-Finnish (FIN)

AF:

0.502

AC:

5314

AN:

10588

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.436

AC:

29575

AN:

67910

Other (OTH)

AF:

0.372

AC:

786

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1913

3825

5738

7650

9563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.423

Hom.:

37047

Bravo

AF:

0.389

TwinsUK

AF:

0.444

AC:

1648

ALSPAC

AF:

0.447

AC:

1724

ESP6500AA

AF:

0.373

AC:

1644

ESP6500EA

AF:

0.437

AC:

3754

ExAC

AF:

0.406

AC:

49326

Asia WGS

AF:

0.337

AC:

1171

AN:

3478

EpiCase

AF:

0.421

EpiControl

AF:

0.421

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 17, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATP6V1B1 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The variant allele was found at a frequency of 0.4 in 249098 control chromosomes in the gnomAD database, including 20838 homozygotes. The observed variant frequency is approximately 357 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP6V1B1 causing Renal Tubular Acidosis With Progressive Nerve Deafness phenotype (0.0011), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Nov 29, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Renal tubular acidosis with progressive nerve deafness

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

1.6

PROVEAN

Benign

-0.57

N;N;N

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

0.83

P;.;P

Vest4

0.57

ClinPred

0.034

GERP RS

4.9

PromoterAI

0.025

Neutral

(source)

Varity_R

0.89

gMVP

0.60

Mutation Taster

=162/38

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over